Zosia Chustecka

November 17, 2014

ZURICH — New data on nivolumab used first-line in metastatic melanoma show significantly better outcomes when compared with chemotherapy, and were hailed as "outstanding" when they were presented here at the Society for Melanoma Research (SMR) 2014 International Congress. The study was simultaneously published online in the New England Journal of Medicine.

The 1-year survival rate was 72.9% with nivolumab vs 42.1% with chemotherapy (dacarbazine), with a hazard ratio of 0.42 (P < .0001).

This translates to a 58% reduction in the risk for death during treatment with nivolumab, noted Georgina Long, MD, PhD, from the Melanoma Institute Australia at the University of Sydney, who presented the results at the meeting.

"Nivolumab first-line represents a potential new standard of care," said Dr Long, who also urged industry and regulatory authorities to make this drug available as soon as possible.

Nivolumab is so far approved only in Japan (Opvido, Ono and Bristol-Myers Squibb), but approvals elsewhere are eagerly awaited and anticipated soon.

Another immunotherapy, ipilimumab (Yervoy, Bristol-Myers Squibb), is already approved for first-line use in metastatic melanoma, but the response rate to ipilimumab is low (around 10% to 12%) and the drug has considerable toxicity.

Nivolumab acts at a different point in the immune cascade (it is a programmed death inhibitor), and appears to have a milder profile of immune-related adverse events and a higher response rate (around 30% in previous trials and 40% in the current study).

Nivolumab was initially tested in patients who had been treated with and progressed on ipilimumab. This second-line status is likely to be the initial indication approved for the drug. But this latest study demonstrates its utility in the first-line, which also represents a far larger market for the product.

Dr Long commented that, although ipilimumab was approved for first-line use in metastatic melanoma and is the first drug ever to show an improvement in survival compared with chemotherapy, the standard of care for many patients around the world is, in fact, dacarbazine.

These latest results "put another nail in the coffin for chemotherapy," she said.

Superior to Chemo on Every Measure

The study, known as CheckMate 066 (and also CA209-066), was conducted in Australia, Canada, Europe, Israel, and South America (but not the United States), as these are areas where dacarbazine is often used as the standard of care. The researchers enrolled 418 patients with metastatic melanoma who had not received any previous treatment and who did not have the BRAF mutation in their tumors. They were randomized to receive nivolumab 3 mg/kg every 2 weeks or chemotherapy with dacarbazine (1000 mg/m² every 3 weeks) plus matching placebos in each group.

Patients were enrolled from January 2013 to February 2014, but by June 2014, the safety monitoring committee noted an imbalance of deaths in the 2 groups. They called for an ad hoc analysis of the data, which showed a clear survival benefit for nivolumab, Dr Long said. At that point, the study was unblinded, and patients in the dacarbazine group of the study were allowed to cross over to nivolumab.

The results show significant superiority for nivolumab on every measure.

The median overall survival has not yet been reached in the nivolumab group, and was 10.8 months with dacarbazine.

Median progression-free survival with nivolumab was 5.1 months vs 2.2 months with dacarbazine, and the overall response rate was 40.0% vs 13.9%, with complete responses seen in 7.5% vs 1.0% of patients, respectively.

The median time to first response was 2.1 months for both drugs, and the median duration of response has not been reached for nivolumab and was 6 months with dacarbazine. Patients are continuing to respond to treatment in both groups — 72 of 84 patients (86%) in the nivolumab group and 15 of 29 patients (52%) in the dacarbazine group (although these patients were allowed to cross over to nivolumab when the study was unblinded).

There was also evidence of the unconventional response pattern that is sometimes seen with immunotherapies, the researchers write.

A reduction of 30% or more of tumor burden in the target lesion was achieved or maintained in 17 of 54 patients on nivolumab who were treated beyond progression, but only in eight of the 49 patients in the dacarbazine group.

One of the long-standing issues with these novel immunotherapies is the search for a biomarker that would identify patients who are likely to respond; one potential is the programmed death ligand 1 (PDL1) expression in the tumor.

However, in this study, PDL1 status did not have any impact on the results; there was a significant improvement in overall survival with nivolumab compared with chemotherapy irrespective of PDL1-status.

Adverse events were reported by about 75% of patients in both groups, but grade 3 or 4 adverse events were reported in 12% of patients on nivolumab vs 18% on dacarbazine, and adverse events leading to discontinuation were uncommon, Dr Long noted (occurring in 2% on nivolumab vs 3% on dacarbazine).

"The safety profile of nivolumab is acceptable and manageable," Dr Long commented. The most common advents events reported with nivolumab were fatigue (20% of patients), pruritus (17%), nausea (17%), and diarrhea (16%), and immune-related adverse events affected skin (37%), the gastrointestinal tract (17%), hepatic endocrinopathies (2%), and pneumonitis (2%, all grade 1 or 2). "The vast majority of these immune-related adverse events had reversed at data cut-off," Dr Long noted.

In treatment-naive patients without BRAF mutations, nivolumab statistically significantly improved outcomes compared with dacarbazine, Dr Long concluded.

At the SMR meeting, these results were met with enthusiastic applause and congratulations from experts in the field. Grant McArthur, MB BS, PhD, FRAC, a consultant medical oncologist and director of the skin and melanoma service at the Peter MacCallum Cancer Centre in Melbourne, Australia, said the data were "outstanding."

"I think it's clear now that immune checkpoint inhibitors are a new standard of care and are replacing chemotherapy," Dr McArthur said.

He noted that another presentation at the meeting showed clear superiority for another PD-inhibitor, pembrolizumab (Keytruda, Merck & Co.), over chemotherapy, and noted that this drug had recently been approved in the United States as a second-line therapy. It is intended for use following treatment with ipilimumab, and can also be used in patients whose tumors express BRAF V600, after treatment with both ipilimumab and a BRAF inhibitor.

"One of our challenges now is that we have to work diligently to get access for our patients to these treatments throughout the world," he said.

The study was sponsored by Bristol-Myers Squibb, manufacturer of nivolumab. Dr Long reports acting as consultant or adviser to Amgen, Bristol-Myers Squibb, Novartis, GlaxoSmithKline, Roche, and Merck & Co. Several coauthors also have industry relationships, as detailed in the publication, and three coauthors are employees of Bristol-Myers Squibb. Dr McArthur reports serving as a consultant for Pfizer and Celgene.

N Engl J Med. Published online November 16, 2014. Abstract

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